4X1G

Crystal structure of the hPXR-LBD in complex with the synthetic estrogen 17alpha-ethinylestradiol and the pesticide trans-nonachlor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.25 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.176 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Synergistic activation of human pregnane X receptor by binary cocktails of pharmaceutical and environmental compounds.

Delfosse, V.Dendele, B.Huet, T.Grimaldi, M.Boulahtouf, A.Gerbal-Chaloin, S.Beucher, B.Roecklin, D.Muller, C.Rahmani, R.Cavailles, V.Daujat-Chavanieu, M.Vivat, V.Pascussi, J.M.Balaguer, P.Bourguet, W.

(2015) Nat Commun 6: 8089-8089

  • DOI: https://doi.org/10.1038/ncomms9089
  • Primary Citation of Related Structures:  
    4X1F, 4X1G, 4XAO

  • PubMed Abstract: 

    Humans are chronically exposed to multiple exogenous substances, including environmental pollutants, drugs and dietary components. Many of these compounds are suspected to impact human health, and their combination in complex mixtures could exacerbate their harmful effects. Here we demonstrate that a pharmaceutical oestrogen and a persistent organochlorine pesticide, both exhibiting low efficacy when studied separately, cooperatively bind to the pregnane X receptor, leading to synergistic activation. Biophysical analysis shows that each ligand enhances the binding affinity of the other, so the binary mixture induces a substantial biological response at doses at which each chemical individually is inactive. High-resolution crystal structures reveal the structural basis for the observed cooperativity. Our results suggest that the formation of 'supramolecular ligands' within the ligand-binding pocket of nuclear receptors contributes to the synergistic toxic effect of chemical mixtures, which may have broad implications for the fields of endocrine disruption, toxicology and chemical risk assessment.


  • Organizational Affiliation

    Inserm U1054, Montpellier 34090, France.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Nuclear receptor subfamily 1 group I member 2316Homo sapiensMutation(s): 0 
Gene Names: NR1I2PXR
UniProt & NIH Common Fund Data Resources
Find proteins for O75469 (Homo sapiens)
Explore O75469 
Go to UniProtKB:  O75469
PHAROS:  O75469
GTEx:  ENSG00000144852 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO75469
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
3WG Binding MOAD:  4X1G Ki: 3010 (nM) from 1 assay(s)
3WF Binding MOAD:  4X1G Kd: 1.15e+4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.25 Å
  • R-Value Free: 0.218 
  • R-Value Work: 0.174 
  • R-Value Observed: 0.176 
  • Space Group: P 43 21 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 91.34α = 90
b = 91.34β = 90
c = 85.49γ = 90
Software Package:
Software NamePurpose
PHENIXrefinement
XDSdata reduction
XSCALEdata scaling
PHENIXphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History & Funding Information

Deposition Data


Funding OrganizationLocationGrant Number
ANR CESAFrance--
Plan Cancer InsermFrance--

Revision History  (Full details and data files)

  • Version 1.0: 2015-09-09
    Type: Initial release
  • Version 1.1: 2015-09-16
    Changes: Database references
  • Version 1.2: 2018-07-04
    Changes: Data collection, Structure summary
  • Version 1.3: 2024-01-10
    Changes: Data collection, Database references, Refinement description